1. Field of the Invention
The present invention relates to compounds having a tricyclic pyrazolotriazolopyrimidine ring structure which possess antagonist activity for adenosine receptors, particularly the A1, A2A, A2B, A3 adenosine receptor subtypes. In particular, the invention relates to new compounds having a tricyclic pyrazolotriazolopyrimidine ring structure, methods of synthesis for those compounds, and methods of using those compounds for modulation of biological function in the nervous, cardiovascular, renal and immune systems of a mammal and methods for treatment of a mammal suffering from or susceptible to diseases or disorders associated with adenosine bio-activity in the nervous, cardiovascular, respiratory, renal and/or immune systems of the mammal.
2. Background
Adenosine, an endogenous modulator of a wide range of biological functions in the nervous, cardiovascular, respiratory, renal, and immune systems, interacts with at least four cell surface receptor subtypes classified as A1, A2A, A2B and A3. These receptor subtypes belong to the superfamily of G protein-coupled receptors and have been cloned from several animal species.
In the past ten years, great efforts by medicinal chemists and pharmacologists have been devoted to the design of potent and selective ligands for A2A and A3 receptors. Thus, the pyrazolotriazolopyrimidines SCH 58261 (5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine), SCH 63390 (5-amino-7-(3-phenylpropyl)-2-(2-furyl)pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine) and related compounds that possess hydrophilic groups at the para and ortho positions of the aromatic ring have been found to be potent and selective adenosine A2A antagonists, and SCH 58261 is widely used as a tool for characterizing the adenosine A2A receptor subtype. See, for example, (1) Baraldi, P. G. et al, Curr. Med: Chem.; 1995, 2, 707–722; (2). Baraldi, P. G. et al., J. Med. Chem. 1998, 41, 2126–2133; (3). Baraldi, P. G.; et al., J. Labeled Compds. Radiopharm. 1996, XXXVIII, 725–732; and (4). Zocchi, C et al., Br. J. Pharmacol. 1996, 117, 1381–1386. At the same time, different classes of compounds have been reported to be selective A3 receptor antagonists (eight classes with non-xanthine structure, including dihydropyridine and pyridine analogs, flavonoid, isoquinoline and triazoloquinazoline derivatives, triazolonaphthiridine and thiazolopyrimidine analogs). The best results in terms of A3-antagonism were obtained with 5-N-(substituted phenylcarbamoyl)amino-8-substituted-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines, which are substituted on the phenyl ring of the phenyl carbamoyl moiety with a para-methoxy group or a para-chloro group ((1) Baraldi, P. G. et al., Trends Pharmacol. Sci. 2000, 21, 456–459; (2). Braldi, P. G., et al., J. Med. Chem. 1999, 42, 4473–4478; and (3). Varani, K.; et al., Mol. Pharmacol. 2000, 57, 968–975).
Attempts to modulate the metabolism of adenosine, thereby increasing the endogenous levels have been examined. In rodents, the use of adenosine deaminase inhibitors to prevent the rapid deamination of adenosine to inosine was shown to greatly enhance the effectiveness of spinal morphine in reducing allodynia. A similar effect was observed with the intrathecal administration of nucleoside transport inhibitors that slow or prevent the cellular uptake of circulating adenosine. Adenosine kinase inhibitors, which prevent the phosphorylation of adenosine to adenosine monophosphate, have also been reported as effective (Lynch et al, Eur. J. Pharmacol. 364: 141–146 (1999); Kowaluk et al, J. Pharmacol. Exp. Ther. 295: 1165–1174 (2000); Suzuki et al, Br. J. Pharmacol. 132: 1615–1623 (2001); Zhu et al, Brain Res. 905: 104–110 (2001)). All of these approaches act by increasing the concentration of adenosine available to the adenosine A1 receptor.
Investigations of other modulation of adenosine receptors have been reported in Bruns et al., Mol. Pharmacol. 38: 939–949 (1990); Bruns et al., Mol. Pharmacol. 38: 950–958 (1990); Bruns et al., Mol. Pharmacol. 38: 939–949, 950–958 (1990), Leung et al, Naunyn-Schmied. Arch. Pharmacol. 352: 206–212 (1995); Baraldi, U.S. Pat. No. 5,939,432; Baraldi et al, Bioorg. Med. Chem. Lett. 10: 1953–1957 (2000); van der Klein et al, J. Med. Chem. 42: 3629–3635 (1999); Kourounakis et al, Drug Dev. Res. 49: 227–237 (2000); and Tranberg et al, J. Med. Chem. 45: 382–389 (2002)).